Environments and their organic content are generally not static and isolated, but in a constant state of exchange and interaction with each other. Through physical or biological processes, organisms, especially microbes, may be transferred between environments whose characteristics may be quite different. The transferred microbes may not survive in their new environment, but their DNA will be deposited. In this study, we compare two environmental sequencing projects to find molecular evidence of transfer of microbes over vast geographical distances.
By studying synonymous nucleotide composition, oligomer frequency and orthology between predicted genes in metagenomics data from two environments, terrestrial and aquatic, and by correlating with phylogenetic mappings, we find that both environments are likely to contain trace amounts of microbes which have been far removed from their original habitat. We also suggest a bias in direction from soil to sea, which is consistent with the cycles of planetary wind and water.
Our findings support the Baas-Becking hypothesis formulated in 1934, which states that due to dispersion and population sizes, microbes are likely to be found in widely disparate environments. Furthermore, the availability of genetic material from distant environments is a possible font of novel gene functions for lateral gene transfer.
Copyright: © 2008 Hooper et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the EU 6th Framework Programme, Contract Nrs LSHG-CT-2004-503567 (GeneFun) and LSHG-CT-2003-503265 (BioSapiens). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The advances of environmental sequencing projects, or metagenomes, have brought methods and concepts from molecular biology and comparative genomics to the field of microbial ecology. Many of the same tools that are used in the analysis of isolate genomes can now be applied to whole communities of organisms . In this work, we perform what can be described as comparative metagenomics, where we attempt to identify genetic material that originated from outside the environment, possibly transported by physical processes such as wind or water. For instance, dust clouds may carry microbes over vast distances , and carrier organisms such as birds and humans  are potential vehicles for transporting microbes. In other cases, drainage from cultured soils may pollute water , and it is conceivable that microbes may be transferred in the process.
The motility and sheer numbers of microbes form the basis for the Baas-Becking hypothesis formulated in 1934 . It can be summed up as follows; everything is everywhere and the environment selects. For instance, the hypothesis implies that there is a good chance of finding trace amounts of a wide range of bacterial species wherever we look, but this does not mean that the species will grow or even survive in its new environment. Even if the transported microbe is inert, it would still contribute its genome (and DNA) to the new environment. Thus, the transported DNA may remain packaged within an inert host, within a surviving host, or may be free as the result of a ruptured or digested cell. Free-form DNA has been observed in for instance ocean sediments , where it comprises up to 90% of all DNA.
Regardless of the fate of the specific microbe, its DNA can be captured and detected at the time of a metagenomic sampling. Depending on the frequency of the DNA, reads will assemble into contigs or appear as single-reads, and can then be analysed computationally. In this work, we examine two such metagenomes: the Minnesota farm soil  data set and the Sargasso sea  data set, and attempt to evaluate the interchange, if any, of microbes between them using DNA sequences as proxies. Thus, we will evaluate the Baas-Becking hypothesis by examining the proportion of sequences that i) appear very different from other reads in its set and ii) appear more similar to reads in the other set. We will then study those sequences to which are potentially results of a microbe transfer across environments.
This comparative process is conceptually very similar to the study of lateral transfer genes (LGT) in isolate genomes. There is an extensive literature describing this approach, from early but seminal studies using atypical nucleotide composition as indicators of LGT – to extensive phylogenetic studies covering hundreds of genomes . All approaches require a careful choice of characteristics to use as discriminators of whether a sequence appears to be typical or not for its genome. We will substitute genomes for metagenomes in this study, so special attention must be given to the choice of discriminators.
We chose three distinct characteristics as discriminators; two nucleotide composition measures and one protein orthology measure. The first measure is based on the guanine/cytosine (GC) content of the sequence. GC content has been found to vary not only between species but also between environments . For the farm soil and Sargasso sea data sets (hereafter referred to as soil and sea), we observe clear differences in the overall GC content. Soil has a high GC content at 61%, compared to only 34% in sea . This difference is even more pronounced when comparing only the synonymous third codon position of genes (hereafter GC3s%) which avoids selection on the protein level. The more pronounced differences in GC3s% than GC suggest a mutational pressure on the choice of base exerted by exogenic factors, as previously described .
The second measure is based on oligomer frequency patterns (OFPs; –). For instance, the OFP of the oligomer TTATA, relative to the occurrences of T and A respectively, differs widely between organisms.One of the first systematic studies reported showed that the composition of dimers is conserved within genomes but different between genomes . Since then many different methods have been developed to capture the genomic signature of bacteria and they have been use widely for either binning of metagenomic data  or the identification of lateral gene transfer .
Superficially, it could be assumed that GC3s% could be included in this measure, but the level of information is distinctly different in three aspects. Whereas GC3s% directly measures the mutational pressure, the OFP measures the effect of mutational context biases. Since OFPs are also normalized by nucleotide content, this measure is largely independent of GC3s%. Finally, since we study more than one base, OFPs are a more sensitive discriminator.
The third measure is based on protein similarity between translated open reading frames in both data sets. The rationale is that if a gene in e.g. soil has a substantially higher level of orthology to proteins in sea, compared to the rest of the proteins in soil, then it is less likely to be a common fixture of soil. If the two environments never interchange material, then we would expect high levels of orthology only for genes coding for highly conserved and ubiquitous functions, such as cell machinery. However, if a transfer of microbes occasionally occurs between soil and sea, we would expect to find non-ubiquitous yet highly orthologous genes.
For each of these discriminators individually, criticisms can be raised. For instance, bacteria which are parasites within soil eukaryotic cells may essentially live in a mini-environment similar to that of sea microbes, possibly resulting in similarities in GC3s%. Furthermore, organisms that are only distantly related but have similar DNA repair mechanisms could appear similar in OFPs. Orthology may also be spurious due to strict conservation of amino acid sequences of proteins, or by random chance.
Despite individual concerns such as those listed above, it becomes increasingly difficult to regard these open reading frames as false positives when all three discriminators are fulfilled.
In this work, we apply the three discriminators to predicted genes in the soil and sea sets in order to find genes that are consistent with an interchange of microbes between environments. This transfer of microbes did not specifically occur from the Minnesota farm soil to the Sargasso sea or vice versa, but from environments which share features with either the farm soil or Sargasso sea data. As both GC content and protein composition correlate with the similarity of environments , , it is reasonable to assume that our three discriminators also account for transfers from environments that are at least geographically close to the sampling points or are of similar consistency , .
Starting with 184,000 genes in the soil set  and 700,000 genes in samples 2–4 from the sea set , we identified 1,216 genes that have a closer hit in the foreign environment than their own. These genes, together with their match in the foreign environment, formed pairs which allowed us to compare their features. To classify whether the GC content of these candidate gene pairs is endogenous in one but atypical in the other environment, we used the average of the two environmental GC3s% averages (48%) as a breakpoint (Fig. 1).
Figure 1. GC3s distribution of orthologous Genes.
Distributions of GC3s for each of 1216 ORF pairs with closer similarity in the foreign environment. Using GC3s% = 48% as a separator (dotted lines), the ORF pairs are classified based on the GC content of its two members. Category A (upper right) is the quadrant where we expect to find possible transfer events from soil to sea, since these pairs have high GC3%s values for both members. Pairs in category B (lower left) have low GC3%s scores for both Genes, which could suggest a transfer from a sea-like environment to soil. Category C (lower right) has typical GC3s% values for both members of ORF pairs. These pairs are likely to be ancient conserved sequences. Finally, Category D (upper left) has atypical values for both Genes, close to the expected given the shape of the GC3% distribution (28 observed, 24 expected). Unsaturated Ks values are green, and pairs with Kn/Ks>1 are red.
Of the 1216 ORF pairs, 284 sea genes had atypical GC3s% values (>48%); a strong over-representation both in absolute terms and in significance (p<10−13), when compared to the expected number of 109 (based on the proportion of all sea genes with atypical GC3%s values). Conversely, the over-representation of soil genes with GC3s%<48% is not as strong, yet significant: 221 compared to an expected 174 (p<10−3).
Quadrant A (Fig. 1) thus represents gene pairs where the soil genes have typical GC3s% values and the sea genes have GC3s% values much higher than the sea average. Accordingly, quadrant B has lower than average soil GC3s% and typical sea GC3s%. Overall, quadrant A has 170% as many pairs as expected and B 127%. However, since sample sizes are unequal, we subsampled the sea set 10 times into random subsamples of a size roughly equal to soil (Table 1). The degrees of over-representation remained at 165% and 123% respectively. Details of quadrants A–D are provided as supplementary Tables S1–S4.
Table 1. Resampling of sea set.
At this point, we have created three classes of genes using orthology and GC3s% as discriminators. These classes represent genes that may have been transferred into a new environment (quadrants A and B) or simply conserved genes (quadrant C). If all three classes are actually false positives, we would expect OFPs to be distributed according to random expectation, i.e. soil genes would have OFPs similar to the soil set in large, and analogously for sea genes. Out of 16,450 random soil genes, 14,040 map to soil (85.3%). For sea, 14,257 of 16,476 map correctly to sea (86.5%). Thus, we expect that of the 284 soil genes in A, 242 should map to soil. However, we observe that only 53 soil genes map better to soil than sea. This is a strong under-representation (p<10−137). In quadrant B, we expect that 191 of the 221 sea genes would map to sea, but observe only 13 (p<10−161). The OFPs of quadrants A and B, compared to soil and sea sets are visualized as chaos game representations (; see methods) in Fig. 2.
Figure 2. Chaos Game Representation (CGR) plot of oligomer frequencies of A and B vs soil and sea patterns.
Note the similarities between A and soil, and B and sea respectively. Figure intensities have been normalized for clarity. CGR plots are a way of visualizing chain processes, such as oligomer patterns. See methods for details.
Finally, as an additional control, we study genes in quadrant C, which we do not believe to be transferred. Here, we find 674 of 678 unique sea genes and 579 of 663 unique soil genes mapped to their own environments. The sea mappings are actually significantly over-represented (p<10−14), and soil genes map to soil about as often as expected.
The results strongly imply that genes in quadrants A and B are not only atypical in their current environments, but also highly similar to the external and internal mutational pressures in the other environment.
Amino acid identity is a measure of the similarity between the amino acid translations of genes, and as such focuses on the non-synonymous bases. A further comparison would be to measure the synonymous substitution rate Ks  of a gene pair, since this rate quickly becomes saturated over time. A Ks value of over 2.0 suggests that each base has on average been substituted at least once; changes are therefore saturated. However, values of less than 2.0 suggest a higher level of similarity than evident from amino acid identities. Finding such unsaturated pairs in the quadrants would further suggest a shared recent history. In quadrant A we find 87 such pairs, and in B 31. Again, this is not what we expect if we consider the gene pairs to simply be ancient homologs. In quadrant C for instance, which we consider to be composed mainly of ancient homologs, we find only 8 unsaturated pairs out of 667. None score lower than 1.2. Thus, unsaturated gene pairs are significantly overrepresented in quadrants A and B (both at p<10−14). Furthermore, the ratios (87 to 31) again suggest a bias in directionality from soil to sea. This also holds when the datasets are resampled (Table 1), suggesting that it is not an effect of sample sizes.
If genes in quadrants A and B are the results of microbes, alive or not, traversing large distances between soil and sea, then it would be interesting to know which species they come from. Determining which taxa are included in a metagenome is referred to as binning, and is not a straight-forward task. Since the focus of this paper is not on binning Minnesota farm soil and Sargasso, we employ a simple best hit approach and record the species for each gene. The results were then mapped onto the Interactive Tree of Life  and are available as supplementary figures (Fig. S1–S3).
For quadrant A, which should represent transfer from soil to sea, we find a relatively even contribution from a wide range of phyla and a considerable (∼25%) contribution from the Rhizobium/Bradyrhizobium clades. Both of these families are predominantly terrestial bacteria, which is consistent with our findings.
Similarly, in quadrant B, we also observe an even contribution from a wide range, with a stronger representation from the bacteroides genus. Bacteroides are not predominantly soil bacteria, but can be found in the guts of farm animals. It is hence not subject to the mutational pressures of soil but is readily and consistently transferred from animals to soil. It is therefore not inconceivable that the contribution of bacteroides may be via animal waste to soil, and then to sea. This does not weaken our results, but rather strengthens the conclusion that transfer is predominantly from soil to sea rather than vice versa, and underlines the interaction of diverse environments other than the two we have studied.
For comparison, we include best hit binnings for the whole soil and sea sets (Fig. S4–S5). Noteworthy is the huge dominance of Candidatus pelagibacter (e.g. ) in the full sea set, but which is largely absent in quadrant A. Furthermore, our simplistic binning approach suggests that there is no strong contribution from any potential lab contaminant.
The null hypothesis is that the transferred DNA is selected randomly, and therefore codes for random products. Supplementary Table S5 illustrates the distribution of protein functions by Cluster of Orthologous Gene categories . Generally, quadrants A, B and C are consistent with a random selection of functions drawn from the distributions of the whole metagenome sets, but some differences nonetheless stand out. Quadrant B has lower numbers of ORFs coding for energy production and conversion and general function prediction (COG category C and R) than quadrants A and C, but higher numbers of ORFs coding for translation, replication and repair.
Based on our studies, quadrants A and B are consistent with a transfer effect. But what of the fate of these transported genes or DNA fragments? Most likely they will simply be degraded, but there is also a possibility of incorporation into indigenous genomes, constituting a true LGT. We can first study the GC content of the flanking DNA or neighboring gene, if any, and see if it is different or similar. Of the 505 candidates, the majority of flanking DNA has similar GC values. This suggests that large regions (likely entire genomes, plasmids or chromosomes) have been transferred but not assimilated. In quadrant A however, 31 of 284 sea genes have one or more neighbors with a GC3s%<48%, which may suggest that some genes are occasionally integrated into indigenous genomes. In this case, the ability to assemble contigs with several genes also suggests that these genes may have been incorporated into abundant species. Furthermore, we studied transfer candidates that seem to be under positive selection, as this would indicate an adaptation to the new environment and therefore LGT. We find 8 ORF pairs that suggest an accelerated evolution (Kn/Ks>1): 7 in quadrant A and 1 in B. The annotated functions  of these ORFs in the process of adaptation are diverse (Tables S1–S2). However, the function that is under selection is not necessarily the same as the annotated function  so we cannot exclude a common functional theme due to the process of adaptive radiation . Unfortunately, only 2 of the 7 ORFs have neighbors – both with similar GCs% values. This would suggest that these adapting ORFs may have been incorporated along with other genes which are not under selection in the new environment. Moreover, given the high rate of amelioration at the synonymous base, it is likely that many such ORFs would have Kn/Ks<1 despite adaptation. These 8 ORFs are therefore a conservative estimate.
Through several different comparisons, we have found a set of genes, however small, for which the simplest explanation is microbe transfer. Specifically, we seem to detect a transfer of genetic material in the Sargasso samples from an environment very similar to Minnesota soil and vice versa. Given the prodigious population sizes and motility of e.g. bacteria, it should not be a surprising conclusion. However, detecting it is not as intuitive, and we believe we are the first to address this question using computational methods.
Our data is for natural reasons limited; other oceanic and soil samples may contain other transfer candidates, and the total transfer to the Atlantic Ocean from environments similar to Minnesota farm soil must be considerably larger. However, we believe it is an informative snapshot given the current data. With more large-scale sequencing projects, the picture will undoubtedly improve.
We also suggest a bias in transfer from soil to sea, in line with the generally accepted flow of water from land to oceans. Furthermore, the presence of bacteriodiales in quadrant B further tilts the scale in favor of transfer from soil to sea, since they are likely to have originated in a third environment – animal gut. Assessing the total proportion of foreign DNA in a metagenome is a difficult task at best. In this study, we focused on sets with quite different nucleotide compositions, which simplify detection of foreign DNA. Other sources of transfer may be more similar to the receiving environment, and detection is therefore more complicated. In addition, rare foreign DNA may be present in low numbers and is likely to evade detection by normal shotgun sequencing. Thus, in the case of transfers between soil and sea, the amount of transferred DNA seems to be abundant enough to be detectable by shotgun sequencing, even though it is only a fraction of the amount of indigenous DNA.
This study therefore suggests that the species abundance distributions of metagenomes which are not physically isolated may have exceedingly long 'tails' composed of rare organisms. It is therefore unlikely that sequencing projects of this type will reach full coverage in the near future.
While little data is available on genes which have been incorporated into new hosts, our findings suggest that it is possible. Furthermore, it has been found that the extent of LGT in metagenome samples is comparable to that of isolate genomes , suggesting that LGT is an active process also within the soil and sea microbiomes. Combined with our findings, we suggest that the impact of LGT could be more far-reaching than previously thought, since functions need not be acquired from the immediate vicinity but from entirely different environments. This would also include non-microbial donors, such as genetically modified plants.
DNA with different composition will end up with different coordinates in the plot depending on the symbols. All points are bound to the unit square. Plot intensities have been normalized for clarity. Note that no conclusions have been drawn directly on the figure itself, rather from significance tests of the distributions in the quadrants. The figure is included for visualization purposes only.
We used the same data from Sargasso and Minnesota as were used previously by Tringe and co-workers . Note that this data set does not include sample 1 from Sargasso, due to recent criticism .
Gene predictions were performed by the original authors, resulting in roughly 700 000 and 184 000 ORFs respectively.
Nucleotide sequences were pairwise aligned by ClustalW  using the corresponding protein sequences as an alignment guide. Gaps and adjacent divergent positions in the alignments were removed. KS estimates were obtained with the Codeml  algorithm in the PAML package (F3x4 model, gamma shape parameter and transition-transversion ratio estimated from the data ). Calculations were repeated five times to avoid incorrect Ks estimations due to suboptimal local maxima.
ORF pairs belonging to category A. Sea: Sargasso ORF. Soil: Minnesota ORF. ID: protein identity. Pos: protein positive similarity. Length: Overlap length of overlapping sequence. GC_sea: GC3s% of Sargasso ORF. GC_soil: GC3s% of Minnesota ORF. Diff: GC3s% difference. KaKs: substitution ratio of synonymous to non-synonymous base. Ka: synonymous base substitution rate. Ks: non-synonymous substitution rate. COG: COG assignment. Func: COG functional category. Annotation: predicted function.
ORF pairs belonging to category B. Sea: Sargasso ORF. Soil: Minnesota ORF. ID: protein identity. Pos: protein positive similarity. Length: Overlap length of overlapping sequence. GC_sea: GC3s% of Sargasso ORF. GC_soil: GC3s% of Minnesota ORF. Diff: GC3s% difference. KaKs: substitution ratio of synonymous to non-synonymous base. Ka: synonymous base substitution rate. Ks: non-synonymous substitution rate. COG: COG assignment. Func: COG functional category. Annotation: predicted function.
ORF pairs belonging to category C. Sea: Sargasso ORF. Soil: Minnesota ORF. ID: protein identity. Pos: protein positive similarity. Length: Overlap length of overlapping sequence. GC_sea: GC3s% of Sargasso ORF. GC_soil: GC3s% of Minnesota ORF. Diff: GC3s% difference. KaKs: substitution ratio of synonymous to non-synonymous base. Ka: synonymous base substitution rate. Ks: non-synonymous substitution rate. COG: COG assignment. Func: COG functional category. Annotation: predicted function.
ORF pairs belonging to category D. Sea: Sargasso ORF. Soil: Minnesota ORF. ID: protein identity. Pos: protein positive similarity. Length: Overlap length of overlapping sequence. GC_sea: GC3s% of Sargasso ORF. GC_soil: GC3s% of Minnesota ORF. Diff: GC3s% difference. KaKs: substitution ratio of synonymous to non-synonymous base. Ka: synonymous base substitution rate. Ks: non-synonymous substitution rate. COG: COG assignment. Func: COG functional category. Annotation: predicted function.
A breakdown of COG categories by quadrant. The 'expected' occurence is based on the classification of the full soil and sea sets Cat: COG category. A,B,C: quadrants. Expected: expected number given random occurrence.
Phylogenic distribution of category A.
Phylogenic distribution of category B.
Phylogenic distribution of category C.
Full phylogenic distribution of the Sargasso set.
Full phylogenic distribution of the soil set.
Conceived and designed the experiments: PB SH. Performed the experiments: SH. Analyzed the data: SH DD. Contributed reagents/materials/analysis tools: EH JR KF DD. Wrote the paper: PB JR SH.
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Nurse strike dates 2023: RCN announces more strikes in January and February - which NHS trusts are affected?
Strep A: little girl, 4, almost died when the bacteria turned her chickenpox into a flesh-eating infection
Covid cases are on the rise in England and Wales (Composite: Mark Hall / NationalWorld)
Covid symptoms: 10 most common signs of infection affecting people right now as UK cases rise
Covid infections in England and Wales are continuing to increase, new Office for National Statistics figures show
By Claire Schofield
30th Sep 2022, 2:01pm
Covid cases are continuing to rise in England and Wales, sparking fears of a new wave of infections.
Some 1.1 million people in the UK have tested positive for coronavirus in the latest survey, covering the seven days to 17 September in England and the week to 20 September in the other three nations.
This marks a 14% rise from 927,900 in the previous survey, which covered the week to 13/14 September.
It is the first time the UK-wide total has been above one million since late August, bringing an end to a steady fall in UK-wide infections since early July, when the total hit 3.8 million at the peak of the Omicron BA.4 and BA.5 wave.
Sarah Crofts, ONS deputy director for the Covid-19 infection survey, said it is "too early to identify whether this is the start of a new wave", but Professor Tim Spector, co-founder of the Zoe Health Study, said on Thursday it is "clear we're now seeing an autumn wave of Covid-19, combined with increases in hospital admissions".
Professor Spector, lead scientist on the ZOE Covid study, explained in a recent update on YouTube that one in 37 people now have the virus and the R number up at 1.1. An R number of one means that on average every person who is infected will infect one other person.
He added that infections among all age groups are now "creeping up", particularly among the over 75s.
Prof Spector warned of a potential new Covid variant, named BQ1.1, which virologists are monitoring, but the BA.5 variant is currently still dominant.
As case numbers are rising across the UK, Prof Spector issued an update on the most common symptoms being logged on the ZOE Covid Study app. Listed are the top 10 symptoms of Covid to be aware of right now.
1. Sore throat
A sore throat is currently the most common Covid symptom on the ZOE Covid app, reported by 68% of users. It typically tends to occur in the early stages of infection and drinking plenty of fluids should help to ease the pain.
2. Headache
A headache is often one of the earliest signs of infection and is now much more common than a fever, or loss of taste or smell, with 55% of people reporting this symptom on the ZOE Covid app. A study in Norway also found that people infected with Covid tend to have moderate to severely painful headaches, or feel pulsing or stabbing pains.
3. Cough (no phlegm)
Widely recognised as one of the 'classic' Covid symptoms, a dry cough will typically affect around four in 10 people who test positive, according to the ZOE Covid study. A persistent cough means coughing many times a day, for half a day or more, and it will usually be very dry.
4. Blocked nose
A blocked nose is commonly associated with a cold, but it is increasingly being reported as a symptom of Covid, with 51% of ZOE Covid app users saying they suffered from it. Nasal sprays or drops may help to provide some relief.
Office for National StatisticsEnglandCovid-19

redpajama_set_name: RedPajamaCommonCrawl


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Home » Drug Delivery » Analysis
What is Pfizer? Profiling the company behind the vaccine newly-approved in the UK
Drug DeliveryDevices
By Peter Littlejohns 03 Dec 2020
The Covid-19 vaccine from Pfizer may signal hope for an end to the pandemic, but the company's rich history invovles major failures as well as successes
The vaccine from Pfizer and BioNTech has been approved for use by the UK regulator (Credit: Shutterstock/Seda Servet)
Pfizer could be about to enshrine its name in history as one of a few companies to offer hope for an end of what is one of the bleakest moments in recent modern history.
The company and its collaborator BioNTech have received approval from the UK Medicines and Healthcare products Regulatory Agency (MHRA), and will be deployed in the country from next week.
But prior to the vaccine's development cycle, which inevitably became prominent news internationally, the average layman may have gone a lifetime with no knowledge of what Pfizer is, how it has contributed on the healthcare stage, or that it once dabbled in the world of medical devices – and made some catastrophic errors.
Here, we take a look at how the company got started as well as some of the notable achievements and controversies to which it has been central.
What is Pfizer?
The history of Pfizer begins in the 19th Century, when German-born Charles (originally Karl) Pfizer emigrated to America in 1948 alongside his cousin Charles Erhart.
The two made the voyage with ambitions to combine the chemical preparation and compounding expertise of Pfizer with the confectionary skills of Erhart to create the chemicals business Charles Pfizer and Company.
They bought their first factory in Brooklyn, New York, using a loan of $2,500 – equivalent to $84,000 today – given to Pfizer by his father.
Initial achievements included the production of Santonin, which stunned or outright killed internal parasites, and the mass production of citric acid, which the company quickly found a market for among soft drink giants Coca Cola and Dr Pepper, both of whom used it extensively in products.
The older of the two, Erhart, died in 1891 at 70 years old, followed later by Pfizer in 1906.
After the death of Charles Pfizer, the company passed into the hands of his youngest son Emile, who served as president until 1941.
Emile was the last relation of the founders to run the business, and since then it passed through many hands until, like most multinational giants, its ownership was split between a patchwork of investors and stakeholders.
Today, Pfizer is the 49th-largest publicly traded company in the world, with a market capitalisation of about $210bn.
It wasn't long after Emile Pfizer took control of the company that the first world war kicked off and caused a shortage of calcium citrate, a substance extracted from unripe citrus fruit it imported mostly from Italy – and a key ingredient needed to make citric acid.
The need to find an alternative way to develop its popular product led Pfizer to hire food chemist James Currie, who had discovered that fermenting the common fungus Aspergillis niger with sugar created citric acid.
After several years of experimentation, Pfizer's scientists managed to scale up the production of citric acid using deep-tank fermentation – a process that allows for high-volume, continuous fermenting.
While this effort was applied in the name of maintaining its position as the key supplier of citric acid, it actually led to even more growth for the company, as the new production cycle meant much greater supply than the previous one.
The crowning achievement of Pfizer's work in deep-tank fermentation, though, was that once the second world war came around and demand grew enormously for Alexander Fleming's wonder drug penicillin – developed using a similar fungus-based fermentation process – the company had the tools needed to manufacture the antibiotic at a rate great enough that allied soldiers carried a vial with them when they stormed the beaches at Normandy.
Since then, Pfizer has attached itself to several drugs with household names – although sometimes through mergers with their original manufacturers – including the statin Lipitor, the anti-inflammatory Feldene, and the anxiety treatment Xanax.
Perhaps the most famous of its creations however, was the little blue pill synonymous with treatment for erectile dysfunction, Viagra.
Alongside its numerous successes, Pfizer has had a fair amount of very public failures and been party to several controversies.
It's not abnormal for pharmaceutical companies to have a history of settled lawsuits, and while that doesn't always indicate that their drugs were at fault, Pfizer lost a high-profile case in court over one experimental trial on the African continent.
The company was sued by the Nigerian government for conducting an experimental trial on 100 children with its antibiotic Trovan in 1996 at the height of a meningitis outbreak.
Pfizer insisted that the 11 deaths and multiple children suffering brain damage, paralysis or slurred speech were a result of meningitis, not their drug – but in the end it settled in court for $75m.
In an earlier example of controversy, Pfizer bought a company that produced artificial heart valves in 1979.
One model of the Bjork–Shiley heart valve manufactured by Shiley Laboratories and then by parent firm Pfizer after the acquisition caused the deaths of 500 people when defective valves failed, leading to a lawsuit in 1994 in which the United States ruled against Pfizer for $200m.
The Bjork-Shiley valve wasn't the only foray into medical devices for Pfizer though, as it acquired Hospira – a prominent manufacturer of infusion pumps – in 2015 for around $17bn.
The venture was short lived, however, and Pfizer either sold off or retained parts of the biosimilars and injectables business, it sold its stake in the medical devices wing to ICU Medical in 2016 for $1bn.
While this particular aspect of Pfizer's history isn't controversial, the subject of its acquisitions has come under scrutiny for due to a long-standing effort to lobby the US government on tax reform to reduce its expenditures.
The company has made several attempts to re-domicile itself through M&A activity to reduce its tax burden, one of which involved acquiring UK-based competitor AstraZeneca, which would have created the biggest Big Pharma company in the world.
In 2014, after a drawn-out process of bids, as well as input from parliament, AstraZeneca ruled out the deal under the grounds that it appeared to be less strategic and more geared towards corporate tax benefits.
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A green lane run is a drive through forestry land and can range from gentle tracks to open bog, all driven at a leisurely pace. Spectacular views are usually encountered along the way and the kids enjoy playing in the trees.
Fun days are normally held at a quarry near Broughshane, Co. Antrim and are a chance for members to try their off-road skills. Particularly suitable for new members or novices who can tackle sections at their own pace and there should be plently of members willing to take you for a driving lesson.
Weekend events usually something for all the family (even the ones who don't like land rovers!), these have been held in England (Langdale Quest), Scotland (Drumclog), Ireland (Rathe House) and other exotic places such as Portrush (Benone Strand). Accomodation is normally in a caravan, tent or a lwb land rover.
Shows for those who are so proud of there landy and just want to share the joy with others (or are just too scared to get it scratched offroading). whatever the reason just bring along your pristine Series 1, brand new Range Rover, or 90 pickup farm hack and have a bit o'crack chatting with the lads. Polishing of vehicles is not nescessary as prizes are normally given to the muckiest land rover.
THE SMALL PRINT: While we try to ensure these events are non-damaging we have no control over driver error. Due to the possibilty of driver error, or one of the rocks that mysterious appears under your vehicle, we recommend underbody protection such as diff and steering guards, please contact any club member for advice. Also, each vehicle must be road legal (i.e. taxed and mot'd) for most events except those on private land, each vehicle will be scrutineed for safety reasons at each event. Ropes, shackles, ladders, hi-lift jacks, kerrs, winches are welcome additions to any vehicle but you MUST ensure you are fully conversant with the safety implications before you use them, if in any doubt please ask.


Planet JUPITER, the Controller of Dharma(Good Deeds & Benevolence) in the Solar System.
The planet Jupiter is ruling Sagittarius and Pisces, the 9th and 13 sign of the zodiac and rules number 3.
People either born on 3, 12,21 or 30 OR on Thursdays or in December or March are primarily ruled by Number 3= Jupiter.
This planet gives, command, control, love for discipline and ethics but at the other end could make one dictatorial or too bigoted in opinions (religiousness gone to extreme).
Jupiter is said to be the law maker- the person who lays down law- people influenced by this number want laws/rules- hence could make many enemies in the process. Jupiter is karaka/signifactor of 5th and 9th and also 2nd house- so it does represents children, wealth flows, dharma and luck.
In true sense it's the planet of expansion. It is a planet for friendships, socials and well being.
People influenced by Jupiter are generally ambitious and warm, but may be careless about money. They invariably are at the top- but in doing so they might stress their nerves.
Jupiter aspects with maximum energy the houses, 5th, 9th and 7th from the place it is placed in your horoscope.
Unless ruling a malefic house ( 6th/8th or 12th), Jupiter is a great benefic and make you blessed!
If you are born on 3,12,21,30 or Thursdays. Or Jupiter is strong in your chart or your ascendant or moon sign is Sagittarius or Pisces.
See how your Thursday or dates 3,12,21 or 30 go. Do you make good money, or you have good friends, you have great compassion and love for nature or you like conventions- then you might be a jupiterean.
Your health : Nerves need to be taken care of so is liver and basic digestion. Skin has to be kept healthy with exercise.
Your Lucky Stone : Yellow sapphire or topaz.
Note 9= 3×3 and 12=3×4, so one can clearly see that pure Jupiter value are in the Sign Sagittarius(9th sign = 3 x 3= Jupiter X Jupiter) , which is followed by the mental sign of Jupiter, that is Pisces( 12th sign = 3×4 = Jupiter X (Rahu or Uranus)), causing Pisces people being insecure about money(Rahu/Uranus causes insecurity in minds- especially for money)- but rest of the Pisces qualities are mostly same as Sagittarius, as both are ruled by planet Jupiter.
Jupiter is a benefic by nature. The units of movement of guru/Jupiter is 5-15 units. Guru hives the knowledge and happiness.
Jupiter is amongst the ministerial planets and also venus.The deity ruled by Indra.Its a male planet.
Planet Jupiter or guru represents space in terms of panchamahbhutas.
Jupiter and Venus(shukracharya ) are Brahmins by caste.
The planet Jupiter is sattvik(pure), Venus and mercury are Rajasik- it is a guna/quality, and mars and Saturn are Tamasic in nature.
Jupiter's has knowledge of ancient texts and also modern texts of knowledge, it has a big body and tawny(yellowish brown) body and hair. The phlegm is higher and Jupiter tends to be more intelliegent.The abodes of Jupiter, that is where it can be found is treasure house.
Note Jupiter is ruled by number 3, the number for prosperity. A duration of month is for Jupiter, just like for muhurtha we look at moon position.
The taste of Jupiter is sweet, a weak Jupiter we know causes diabetes- that is problems with sweetness.
Jupiter is a planet of east so is strong in east. People with strong Jupiter generally are born or get attracted to eastern cultures. Trees ruled by Jupiter are with fruits. Saffron colored robes are ruled by Jupiter. That is of a monk.
During the dark half malefic are strong(that is sani/Saturn, rahu/ketu). Benefics acquire strength in the bright half of the month.
Hemant ritu(early winter) is ruled by Jupiter. Guru rules jivas.Jupiter is exalted in cancer.


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GTC18 - The unrelenting optimism of Jensen Huang
Anyone who has seen or hear NVIDIA founder and CEO Jensen Huang speak will attest to his passion, optimism and love of superlatives.
Throughout the GPU Technology Conference, he fielded questions about the announcements that were made with the bouncing enthusiasm and focused patience that has made NVIDIA what it is today.
Here is a round-up of the most interesting comments he made throughout the week.
On self-driving cars and Uber - "Hopefully, we all learn something from it"
NVIDIA's announcement of the simulated self-driving car testing environment was particularly timely considering the recent pedestrian death that shut down Uber's testing operation.
When asked about the incident Huang responds, without downplaying the situation, that the industry needs to pause and demonstrate 'good engineering practice.'
"What happened is tragic and sad but is also a reminder of why we are doing this - because we want to save lives," he says.
"Uber does not use NVIDIA's drive technology. Aside from that, we are looking forward to their investigation to see what they learn, and hopefully we all learn something from it. This is obviously an important moment and as an engineer, as somebody who cares about safety a great deal, and as an important member of this industry - the whole industry will learn from this."
On the NVSwitch's unusually small market - "If the work they do will change the world, I would do it"
The NVSwitch is, excuse the term, an insane piece of hardware designed specifically for AI researchers and deep learning scientists who need high-performance computing.
When someone asks why Huang would approve a project with such a specific use case he doesn't even hesitate to answer.
"The market is not infinitely large but unless we build it we will never know how large," he says.
"But I do know that AI researchers are going to love this because they have been clamouring for larger and larger GPUs and now we've made the ultimate large GPU… If I take 20 workstations, their memory is only half of one DGX2.
"Because there is no other way to do it, because we know how to do it, because only we can do it, even if there are only 100,000 scientists who will benefit from it but the work that they do can change the world, I would do it."
On US/China trade relations - "I don't like wars of any kind"
Another hot topic that Huang was faced with was how the tensions and 'trade war' between China and the USA will affect the continuing development of NVIDIA's technology.
"It is definitely better and vitally important that the world continues to have a collaborative trading and open business relationship," he says.
"China is about one third of NVIDIA's business," he adds before outlining NVIDIA's contribution to the local market through partners and system integration of its products.
"To think about today's global companies as one country or another country I don't think really makes sense," he notes.
"And I use China, but it's true with India, it's true with the UK, it's true everywhere. The question is: for companies that are global how should we think through that? I think the best way is for our nations to figure out how to collaborate."
Jensen Huang - "Anybody who buys NVIDIA's product is my friend."
There is a sense of facetiousness in the above comment but there is definitely truth there as well.
Even when asked if he saw the GPU hitting a barrier akin to Moore's Law he says, "the only barrier is physics and we're good for the next ten years."
Huang is a man who wants the best. The best for himself and his family, the best for his company, and the best for the world at large.
GTC is the perfect place to see how all three of these aspects of this man combine into products that aim to revolutionise the way we interact with the world.
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The period from 2009-2013 was pretty grim for me. A lot was going on internally and externally and it was in 2013 that I reached my 'lifetime low'. My rate had fallen from Rs.46/dollar in 2009 to Rs.63/dollar in 2013. For my serious downfall, some blamed the UPA government's mismanagement and some blamed it on the reviving US economy, while some even made it a superstitious thing and blamed it on my new symbol – ₹! All in all, it was a mixture of both micro and macro-economic factors that led to my free fall.
But in 2014 entered a new government, with new promises and new plans. And I was assigned a new boss – the highly qualified Mr.Raghuram Rajan. So, while, the government made policies to attract more dollars through the FDI route, Mr. Rajan (RBI Governor at the time) enforced plans (such as the currency swap facility) to stabilize the rupee. Thanks to this plan, over $30 bn flowed into India in 2013. And an inflow of more dollars always means a stronger me!
you pump more of it and I feel strong, but an overflow and I go weak!
So my situation was getting better and I was growing stronger. Since then, the only factors working against me were external to my system – Brexit and USA's efforts to increase interest rates. Both these events made our economy look risky and investors shifted their money to a safer and attractive USA.
Despite all these, my balance of payments situation remained strong because there was a restriction on gold imports and a fall in oil prices and the government was pro-FDI. So these moves brought in lots of dollar bills and made sure not much of goes out! Everything was working in my favour.
Most people with black money found other people, without black money, to deposit their savings into the banking system for them.
Not to forget, the exercise led to a cash crunch in our economy, put pressure on our banking system, led to a slowing of businesses, loss of jobs, a fall in GDP (from 7.9% to 6.7%) and an economic loss of a little over Rs. 1,000 bn. The only positive side of it all was a rise in digital transactions and a change in people's behaviour towards saving and investing.
So you see it has been a roller-coaster ride for me. There were months when I'd be up, due to a reduction in oil prices, Trump's skeptical political agenda, Modi's pro-FDI agenda, and GST implementation. And there were months when I was down. That's when people used negative adjectives like tanking, nosedive and rupee free fall to describe my serious condition. At one point I was so critical, my rate almost touched the Rs.75/dollar mark in 2018. While my affair with other countries was mostly to blame for my situation, everyone else made it about the ruling government's poor implementation. They even compared my state to my condition in 2013! Made it a political debate and parties blamed each other for the damage. But in reality, it was due to a lot of macro factors – Crisis-hit Turkey and US-China trade war.
Companies were afraid, markets tumbled, and everyone was worried for the economy, except for exporters who were getting more dollars for their exports!
Everyone spoke about their inflation fears, ignorant to the fact, that I had actually outshone some of my peers – the Argentine peso, Turkish lira, Brazilian real, Russian ruble and South African rand, all thanks to our strong fundamentals (i.e. our GDP growth).
Then there was that time when I slipped badly again, due to oil and put the country in massive turmoil. This double whammy of oil prices rising to $100 per barrel and the increasing rising dollar in the range of Rs.73-75/dollar hit me hard! 2018 was just a bad year for me.
While all this was happening, things back at home were not much better. I was stuck in the ongoing tussle between the government and the RBI which left me highly stressed. From Rajan to Patel, finally, I am now at Das's behest.
Note that a government runs the country, while the RBI carries out its financial transactions.
And when this relationship breaks, it leads to conflict. So first in 2016, Mr Rajan resigned after he felt the lack of support from his political bosses – Mr Jaitley and PM Modi, and then his successor Mr Urjit Patel resigned in 2018, citing 'personal reasons'. TBH, I saw this coming because weeks before his exit, the RBI and the ruling government were at loggerheads over how much freedom RBI should get to limit lending to the government. So now I'm under the control of Shaktitkanta Das for the next 3 years at least. And like they say, third time's a charm let's hope his reign lasts!
In all this, one good thing that did happen was Aadhaar. Thanks to which tracking me has got easier and so has my entry into places. But be warned all these linkages are totally voluntary except for on TRACES (IT website)! From acting as an ID to availing subsidies to opening bank accounts, there's no denying that Aadhaar is useful. But also highly debated when it comes to privacy concerns. So, linking it to all other organizations is solely at your discretion, with the exception of linking it to your PAN card for filing IT returns which is mandatory. This will help the government keep a track of all illegal dealings and hopefully make me strong in the eyes of the world.
While clearly 2018 was filled with more downs than ups, I'm hoping for a positive 2019 with less drama. And hopefully, it's actually started on a good note. In just the second month, the US dollar had got my back and together we got the rupee on track. Post the budget announcement, there has been an increased foreign fund inflow in our markets and it has led to a stronger me. Now, let's just hope this lasts till the end of 2019!


RIMPRO OP 10 by Rimpro India is an octylphenol ethoxylate. Acts as a defoaming agent, dispersant and stabilizer. It is a pale yellow to colorless clear liquid. RIMPRO OP 10 is a type of alkylphenol ethoxylate, composed of ethylene oxide adduct of octylphenol.
Please note, these HSP values are estimations. It is based upon the "like seeks like" principle. It splits an ingredients interactions into three parameters; δD (Dispersion force interactions), δP (Polar forces interactions) and δH (Hydrogen bond force interactions). Hansen Solubility Parameters can help you find a wide range of products that are predicted to be compatible with RIMPRO OP 10. A practical determination of these HSP values would provide higher certainty. Learn More.


You can also find yourself in trouble, by going to jail. In either case, you must make three attempts to roll a double. This allows you to move your game piece around the board to its maximum advantage.
Community Chest Bonus - As in the board game, players will receive a card whenever they land on a deck. If you're successful, you get out of jail and can continue. While each occupies a niche, that's of no help when a player goes on the Internet to learn about a slot machine, whether it's a land-based machine or online casino game, a mobile slot or an Internet computer game. This can be confusing, especially because a half-dozen different Monopoly slot machines exist, licensed by four different companies.
The Jail Bonus provides you with three attempts in which you must roll a double to leave jail. The prize symbols are based on the playing pieces on the Monopoly Board. If not, the bonus features ends and you return to the main game.
Each time a player lands on a property, the mini slot increases the rewards, making them bigger as well as better. Your mover can be moved to property spots, utility spots, or the GO square.
The Chance card allows you to enter into the free spin mode or choose which icons are wild. Players have the option to select a number of game options: Railroad Bonus - If you get the railroad bonus, you will be pushed to the next railroad and will also receive a free roll.
Wild Symbol The wild symbol on Monopoly Slots is the "Top Hat", which on the video screen appears as the funny-looking man with the white mustache, monocle, and top hat. The Community Chest provides either guaranteed wins or free spins. The board game's inception can be traced back towhen Elizabeth J.
Board Bonus Feature Board Bonus is one of the most engaging and detailed features in the Monopoly slot game.
This game has a wild symbol, bonus round, free spins, and autoplay feature. It also allows for cash prizes and bonus rolls. Over half of the spaces on a Monopoly board are properties, so this is a common reward in the game.
As a result, Mr Monopoly can be seen onscreen as he jumps from reel to reel until a wild symbol is chosen. She patented her game in The brick-and-mortar and online versions of this 5-reel, line video slots game feature a wild symbol, scatter symbol, autoplay feature, bonus round, and free spins.
Phillips wanted to explain the single-tax theory of Henry George, as well as illustrate the negative aspects of public monopolies. This symbol substitutes for all other symbols on the game, except the Bonus, Chance, and Community Chest symbols. Instead, a Mystery Wild Bonus is activated randomly.
Big Event This slot machine has a 5x3-reel, line game screen. Like the previous game mentioned, this is produced by Barcrest. These include unique prizes. Around the World Bonus Game Below is a list of different results you might encounter.
It is available for mobile gaming, too. Spartacus Gladiator of Rome Mystery Wild Bonus Similar to the Monopoly board game which comes with several different nuances, the slot machine also treats players to an unpredictable and fun time while offering an opportunity to bag cash prizes.
The company changed its name Williams Electronics in All of the main bonus feature games involving rolling a dice to move around the board, collecting prizes along the way.
The company founded Williams Gaming in in order to enter the video lottery terminal industry. The game proved successful, but IGT sued the company over the electronic reel movements, limiting WMS Gaming's ability to capitalize on their designs.
Once Around Deluxe also has a side bet feature.
Winning combinations are easier to form when Mr Monopoly has chosen a wild symbol. The company's participation slots brought it larger revenues than its games-for-sale did. Also, you receive a free roll.
This gaming machine has nothing in common with the Williams Interactive licensed slots. You collect a slot machine icon, which can be used to collect more rolls or cash.
There are no wild icons in this variation. Monopoly Plus is one of the variations that are highly reminiscent of the legendary game.
This bonus is triggered when a player cannot land on one of the Board Bonus, or Logo symbols on any of the reels. Also, Monopoly has developed its own folklore, such as the myth that Charles Darrow invented the game. It features the fellow in the top hat, but he is holding a wad of cash.
You can also win awards in the form of a cash prize or additional rolls. This dice consists of its own unique prizes which are revealed based on the result of the roll. Monopoly Slots Online Just about all of the Monopoly Slots games you find in casinos involve a bonus game which is based on the famous board game itself.
The game was self-published by Lizzie Phillips inbut she continued to change the rules of the game between that time and the s--changes included the buying and selling of houses. This acts like a free spin bonus mode.
Rising Riches is a video slots game with wilds, scatters, and cascading reels.


If you allow yourself to feel what you really feel, you will eventually get bored with yourself and develop a solution. If you do it in reverse order, the yucky feelings don't ever seem to end.
Will It Be Over Soon?!


An application can be made at the nearest Social Security office near you. In Boulder, the offices are at Suite 101, 4949 Pearl East Circle.
To qualify for a disability claim as an adult, you must show medical evidence of impairment in addition to work details. A claims examiner will look at the impairment, work history and the ability to get a new job.
If you are applying for a child, you must show that the impairments limit the child's ability to participate in activities which other children of the same age are doing normally in studies, sports and so on.
The claimant has a medically determinable physical or mental impairment or both. The impairment should have lasted for more than a year, or be forecasted to last for more than one year.
The impairment must be shown to limit the claimant's ability to work. The limitation is rated according to residual capacity to function (capabilities remains with the claimant that can enable some work). It must be shown that the impairment is preventing the claimant from having work that can bring in sufficient income for basic needs. The claimant must show that he/she has been unable to continue working at a past job, or will be unable to work at a job for which they qualify, on account of the impairment.
Your application is assigned to an examiner who will collect medical and non-medical evidence to support your claim. The examiner will send out requests for your medical records to all the medical providers you have listed as having handled your health case. The examiner heavily relies on the accuracy of this data to make decisions on your impairment. It usually takes under 4 months to get an answer to your application.
If your application is rejected, you can appeal. The case will be assigned to experts specialising in disability matters. The review will take about 2 months. If it is rejected, you can take the appeal to the office of Disability Adjudication and Review and get a hearing before an Administrative Law Judge. An appeal before an ALJ takes longer as there are many such cases.
If you are in Boulder city the ODAR office to go to would be the one in Colorado Springs located at Suite 701, 121 S. Tejon Street.


In Glory Days, Max Lucado draws on the story of Joshua to show how God has a Promised Land for each of us to claim. In God's plan we win more than we lose, forgive as quickly as we are offended, and give as abundantly as we receive.
This study guide with DVD includes a DVD with six video sessions from Max Lucado and a study guide with leader helps, discussion questions, conversation starters, and between-session activities to enhance your understanding and application of Max's teaching.


The Perinatal Services Inquiry engaged in the significant task of examining the quality and safety of perinatal services in Victoria, including services dealing with high risk and premature births, and the quality and safety of current methods to reduce infant and maternal mortality.
As people with disability continue to experience exclusion from social, economic and cultural life in Victoria, this report recommends ways forward.
This Victorian parliamentary inquiry examined responses to criminal child abuse by all non-government organisations that interact directly with children.
The vitality of the Victorian community and its economy is significantly linked with the extent to which older people's participation can be fostered and encouraged.
In a context of tight housing affordability, increasing numbers of Victorians are turning to public housing to meet their housing needs.


text:
Plant Heat up
Nuclear reactor and primary coolant system of WWER-1200.
Source: gidropress.podolsk.ru
used with permission of АО ОКБ "ГИДРОПРЕСС"
In general, a reactor startup after refueling is a startup from a cold condition since refueling requires the Reactor Coolant System (RCS) to be cooled down and depressurized. The initial conditions are: the NSSS – Nuclear Steam Supply System is in the "cold shutdown" mode, which means Tavg = 30°C, pressure = near atmospheric, boron concentration is sufficient to yield 10% shutdown margin, and RCPs – Reactor Coolant Pumps are off. Prior to each point of the procedure above, compliance with the plant Technical Specifications must be verified.
The NSSS heat up from Cold Shutdown (MODE 5) to Hot Standby (MODE 3) is performed by reactor coolant pumps which are very powerful (they can consume up to 6 MW each), and therefore its work together with a decay heat can be used for heating the primary coolant before a reactor startup. Reactor coolant system pressure must be increased to satisfy net positive suction head requirements to operate the reactor coolant pumps, and reactor coolant pumps are started sequentially. The primary plant heat-up rate is limited to about 30°C per hour to minimize internal stress in the material of the pressure vessel, primary piping, and other components.
The RCPs are used because a pressurized water reactor may have a positive moderator temperature coefficient at low temperatures. An operation (reactor criticality) with a positive moderator temperature coefficient caused by the amount of soluble boron in the moderator (see: MTC) is prohibited. Therefore the heat up by chain fission reaction is prohibited. The plant is brought to near operating temperatures (e.g., Tin ~ 275°C) with reactor coolant pump heat before the reactor is made critical. Heat exchangers of the residual heat removal system are bypassed to allow heat up. Since the coolant volume increases (due to thermal expansion) during its heat up, its excess must be removed from the reactor coolant system.
Extensive and intensive properties of the medium in the pressurizer.
Pressure in the pressurizer is controlled by varying the temperature of the coolant in the pressurizer. For these purposes, two systems are installed. Water spray system and electrical heaters system. The submerged electrical heaters are designed to increase the pressure by evaporating the water in the vessel and the heat pressurizer. Water pressure in a closed system tracks water temperature directly; as the temperature rises, the pressure goes up.
When the reactor coolant temperature and pressure reach the target value (e.g., 275°C and 16 MPa), the RCS heat up is finished. The temperature of the coolant is then maintained through the balanced use of reactor coolant pump heat input and a steam dump system that releases steam to the main condenser. The next step in the startup of the plant is to take the reactor critical.
Advanced Reactor Physics:
K. O. Ott, W. A. Bezella, Introductory Nuclear Reactor Statics, American Nuclear Society, Revised edition (1989), 1989, ISBN: 0-894-48033-2.
K. O. Ott, R. J. Neuhold, Introductory Nuclear Reactor Dynamics, American Nuclear Society, 1985, ISBN: 0-894-48029-4.
D. L. Hetrick, Dynamics of Nuclear Reactors, American Nuclear Society, 1993, ISBN: 0-894-48453-2.
E. E. Lewis, W. F. Miller, Computational Methods of Neutron Transport, American Nuclear Society, 1993, ISBN: 0-894-48452-4.
Reactor Startup


Over the past six months, reporters working on a series about high school sports concussions in Oregon have made 235 requests for records — or rather, the same request 235 times. Oregon has one state law to govern how local jurisdictions handle public records. But the responses to this same request are wide and varied across the state.
While we now know that football tops the list of concussion injuries per sport, the focus on football skews concussion discussions about other sports risks of concussion. We explore how to evaluate those risks alongside the benefits of physical activity for kids.
InvestigateWest, the Pamplin Media Group and the Agora Journalism Center are teaming up with high school students and others to investigate concussions among high school athletes. If you're interesting in contributing to this effort please get in touch. We'd especially like to hear from high school students.
Corporate stooge or rural realist?
Oregon Congressman Greg Walden is drawing the ire of net neutrality proponents for opposing FCC consumer protections while receiving contributions from big telecommunications companies. But the story isn't quite as black and white as you might think.
InvestigateWest's work resulted in 13 laws being passed in Washington and Oregon this year, and $48 million in foster care funding being appropriated in Washington. News partners involved in the coverage include Crosscut.com, KCTS9 TV and Pamplin Media Group.
Journalists have to work every day to keep government transparent to citizens. A new batch of laws in Oregon will help them to do that.
Oregon's bedbug secrecy law — who are we protecting?
Unbelievably, the Oregon Legislature gave a blanket exemption from the Public Records Law to documentation of where bedbug outbreaks are going on. Will the Oregon Legislature move forward in the next few days on cleaning up exemptions to the law?
As we enter the last month of legislative debate, here's how public records reform in Oregon is looking, so far, from the vantage of the watchdog press.
Pete Shepherd is a firm believer that nondisclosure can be in the public interest. He has been at the center of Oregon transparency discussions for decades. So who is he?


text:
Q: How can I determine when ng-options has finished updating the DOM? I'm trying to implement the jQuery multiselect plugin using a directive inside my app. Here' the select element:
<select multiple
        ng-model="data.partyIds"
        ng-options="party.id as party.name for party in parties"
        xs-multiselect="parties">
</select>

The model parties model is loaded through $http. The multiselect plugin parses the option elements inside the select and generates the nice multi select.
Is there a way to detect when the select element is populated with options so I can tell the multiselect plugin to update its data?
Here's my directive:
machineXs.directive("xsMultiselect", function() {
    return {
        restrict: "A",
        require: '?ngModel',
        link: function(scope, element, attrs, ngModel) {
            element.multiselect().multiselectfilter();
            scope.$watch(scope[attrs["xsMultiselect"]], function() {
                // I tried watching but it doesn't help
                element.multiselect('refresh');
                element.multiselectfilter("updateCache");
            });
        }
    }
});

A: As discussed in the comments, use
scope.$watch(attrs.xsMultiselect, ...)

I'm not sure when the watch triggers vs when ngOptions updates the DOM.  If you find that the watch is triggering too early, you can try using $evalAsync() or $timeout().  $evalAsync will execute later, but before the DOM renders.  $timeout() will execute later, after the DOM renders.
scope.$watch(attrs.xsMultiselect, function() {
   scope.$evalAsync(function() {
      element.multiselect('refresh');
      element.multiselectfilter("updateCache");
   });
});

or, after the DOM renders:
scope.$watch(attrs.xsMultiselect, function() {
   $timeout(function() {
      element.multiselect('refresh');
      element.multiselectfilter("updateCache");
   });
});

redpajama_set_name: RedPajamaStackExchange


text:
Q: Raster to Ascii by python console in QGIS? I'm working on PyQgis.
I have to convert a raster file to a file .asc. The classic procedure through the Qgis Menu is:
Raster -> Translate (convert format) -> on "Ouput file" select Arc / Info ASCII Grid.
Can this procedure be queried by the python console? What is the command?
EDIT
I tried to run:
processing.runalg('gdalogr:translate', '/path/to/raster.tif',100.0,True,None,0,'',None,False,5,4,75.0,6.0,1.0,False,0,False,None,'/path/to/output.asc')

But the result was:
Error: Wrong parameter value: None

Why?

A: It's probably due to the PROJWIN <ParameterExtent> parameter where you need to specify the extent of the raster layer.
Try running the following:
from PyQt4.QtCore import QFileInfo
import processing

raster = 'path/to/raster'
fileInfo = QFileInfo(raster)
baseName = fileInfo.baseName()
rlayer = QgsRasterLayer(raster, baseName)
extent = rlayer.extent()
xmin, xmax, ymin, ymax = extent.xMinimum(), extent.xMaximum(), extent.yMinimum(), extent.yMaximum()
processing.runalg('gdalogr:translate',rlayer,100.0,True,None,0,'',"%f,%f,%f,%f"% (xmin, xmax, ymin, ymax),False,5,4,75.0,6.0,1.0,False,0,False,None,'/path/to/output.asc')


Having a common center, such that two or more spheres, circles, or segments of circles are within one another.
/con·cen·tric/ (kon-sen´trik) having a common center; extending out equally in all directions from a common center.
describing two or more circles that have a common center.
Having a common center; said of two or more circles or spheres having a common center.
adj 1. referring to a muscle contraction that involves reduction in a muscle's length.
2. referring to muscles or other tissues that are structured as circles or rings.
Historically, GKN Pumps has been an unprofitable venture and, as a result, the seller approached Concentric intent upon a strategic exit from the pump manufacturing business.
8 All interests, in 1331 square metres of business premises along the southern side of Concentric Park Industrial Estate including units 4 - 8 (inclusive) and 10 - 14 (inclusive), to the east of Priory Road, Aston, Birmingham.
In addition to supporting outside projects that encourage developers and designers to think outside the box, Concentric Sky takes great pains in selecting its clients, said Cale Bruckner, vice president of the 55-employee firm.
Concentric achieved this by fixing the inner rotor and adjusting the center of the outer via the use of an eccentric ring.
As the athlete rises, he increases the resistance exponentially throughout the concentric movement.
After 12 weeks of treatment, 18 of the 22 patients in the eccentric loading group had returned to their level of running before injury, compared to eight of 22 who were treated with the concentric regimen.
In response to this need, Concentric tailored an access solution allowing them to ramp up their bandwidth over time.
As Compaq continues to move everything to the Internet, joining with proven Internet service providers like Concentric gives us the ability to quickly extend tailored solutions to our customers with greater confidence," says Ray Frigo, VP of iServices & Solutions at Compaq.
Internet services firm Concentric Network Corp has agreed to acquire New Jersey-based web hosting company 9 Net Avenue Inc for $54m in stock and cash.
Concentric Network Corp, a provider of IP network services, and Microsoft have expanded their partnership with five new initiatives.
You have lower compound inventory in the flow channel, eliminating turbulence and providing a concentric flow of compound to the tooling.
In the same example, the opposite of an eccentric contraction is a concentric contraction, which would be lifting the weight away from the chest.


text:
News from the PlanPhilly team, Feb. 22
PlanPhilly staff
Dear PlanPhilly Member,
After many successful public forums in the riverward neighborhoods, that work is now going to be put into action at the Central Delaware Design Workshop to be held March 1-3 at the Independence Seaport Museum. Principles derived from the forums will be the foundation used by internationally-renowed designers during this three-day period.
After three days of intense work, we believe we'll have exciting broad strokes sketched out for a civic vision for the Central Delaware. We invite you to join us for the public presentation of these first renderings from the design team:
Date/Time: Saturday, March 3, 3:00-5:00pm
Location: Independence Seaport Museum
REGISTER here: www.planphilly.com/registration
The event will be followed by an hour-long reception to thank the designers who participated in the workshop as well as the citizens who have worked throughout this process to make their voice heard. Please register
(www.planphilly.com/registration) so we are able to accommodate for all in the auditorium and the subsequent reception.
We're excited to see the values and principles you've expressed throughout the process get put to paper. The work of the design team will be presented by internationally recognized design team leaders: Peter Latz, Walter Hood, Ken Greenberg, Gary Hack, and Denise Scott Brown. A respondent panel of experts from around the country will provide commentary and criticism and address questions from the audience. Please join us for this exciting next step in the planning process.
In other Planning Process news:
Steering Committee Cancellation
We regret to inform you that the Steering Committee meeting scheduled for Monday February 26 at 8am has been cancelled. Penn Praxis will staff will work to resolve all important Committee issues and update you before the Design Workshop. We will update you on future meetings of the Advisory Group and Steering Committee in next week's email update.
What's New at PlanPhilly
An explosive forum in South Philadelphia: http://www.planphilly.com/node/1032
FEATURE–New waterfront photo slideshow: http://www.planphilly.com/node/1001
New neighborhood coalition formed on the waterfront:
http://www.planphilly.com/node/1033
FEATURE–The facts about riparian rights: http://www.planphilly.com/node/1013
PARTICIPATE–Tell us about interesting places in your neighborhood to post on the website: http://www.planphilly.com/Citizen_Reports
Other Events:
On March 1 at 6:30 p.m., the Penn Institute for Urban Research will host The Next 100 Million: Where Will They Go? The impact of U.S. population growth.
Meyerson Hall
On March 8 at 5:30 p.m., The Delaware Valley Green Building Council hosts an evening of speakers and discussion on Green Infrastructure, featuring a presentation by Howard Neukrug of the Philadelphia Water Department, who spoke at PennPraxis' Best Practices Session February 3.
Carpenter's Hall
Check out www.dvgbc.org for more information.
Thanks for your continued interest and support. We're looking forward to seeing you on March 3,
The PlanPhilly Team
If you would like to unsubscribe to PlanPhilly, click here:
www.planphilly.com/unsubscribe
PennPraxis Office
410 Duhring Wing
University of Pennsylvania School of Design Philadelphia, PA 19104-6311
Brought to you by PlanPhilly
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